Folate (pteroylglutamate) is a vitamin which is a key component in the biosynthesis of purine and pyrimidine nucleotides. Following absorption, dietary folate is reduced to dihydrofolate and then further reduced to tetrahydrofolate by the enzyme dihydrofolate reductase (DHFR). Inhibition of DHFR leads to a reduction in nucleotide biosynthesis resulting in inhibition of DNA biosynthesis and reduced cell division. DHFR inhibitors are widely used in the treatment of cancer (Bertino J., J. Clin. Oncol. 1993, 11, 5-14), cell proliferative diseases such as rheumatoid arthritis (Cronstein N., Pharmacol. Rev. 2005, 57, 163-172) psoriasis and transplant rejection. DHFR inhibitors have also found use as anti-infective (Salter A., Rev. Infect. Dis. 1982, 4, 196-236,) and anti-parasitic agents (Plowe C. BMJ 2004, 328, 545-548). Many types of DHFR inhibitor compounds have been suggested, and several such compounds are used as anti-cancer, anti-inflammatory, anti-infective and anti-parasitic agents. The two general templates of DHFR inhibitors are shown below:

Methotrexate is the most widely used DHFR inhibitor and contains a glutamate functionality which enables it to be actively transported into, and retained inside, cells. However cancer cells can become resistant to methotrexate by modifying this active transport mechanism. Furthermore, non-mammalian cells lack the active transport system and methotrexate has limited utility as an anti-infective agent. Lipophilic DHFR inhibitors which can be taken up by passive diffusion have therefore been developed both to circumvent cancer cell resistance and for use as anti-infective agents. The following publications disclose examples of such compounds:    GB 1345502    U.S. Pat. No. 4,694,007    U.S. Pat. No. 4,376,858    U.S. Pat. No. 4,694,007    WO03002064    U.S. Pat. No. 4,959,474    WO2004020417    WO03031458    WO02068397    Piper J. R., J. Med. Chem., 1996, 39, 1271-1280    Gangjee A., J. Med. Chem., 1997, 40 479-485    Gangjee A., J. Med. Chem., 1998, 41 4533-4541
Agents that passively diffuse into cells will also exit the cell readily and are not retained inside the cell. Both methotrexate and lipophilic based inhibitors give rise to mechanism based side effects. DHFR inhibitors that accumulate in cells in a way that does not depend on the active transport mechanism of methotrexate would be of value. In addition both methotrexate based and lipophilic inhibitors give rise to side effects hence agents that target specific cell types would also be of value.